Over 1 million Americans suffer acute myocardial infarctions each year in the US, and among the survivors there are now 5 million with heart failure. In addition, defects in cell lineage determination or morphogenesis underlie congenital heart malformations, the most common human birth defect. Survivors of congenital heart disease, which number over 1 million in the US, also often suffer from heart failure. Unfortunately, the heart has little, if any, regenerative capacity after injury. The recent technology of human induced pluripotent stem (iPS) cells, developed by Dr. Shinya Yamanaka, has opened the door for novel approaches to human disease. These include the development of human cellular models for understanding disease mechanisms and drug discovery, along with the potential for autologous cell-based therapies. iPS cells are reprogrammed somatic cells that have properties very similar to embryonic stem (ES) cells and potentially provide an alternative to human ES cells for therapy. However the current methods of iPS generation involve viral integration into the genome, precluding their use in humans. We have assembled a team of investigators to develop and capitalize on the potential of induced pluripotent stem cells (iPS) in the treatment of heart disease. These include Drs. Deepak Srivastava, Shinya Yamanaka, Benoit Bruneau and Bruce Conklin, who together bring expertise in the areas of pluripotency, cardiac differentiation, signaling and human genetics. The multiple PIs will work together to address the specific aims with overlap of expertise from several PIs within each aim. This multidisciplinary approach will combine strengths in iPS technology with leaders in microRNA, chromatin remodeling and signaling as they relate to cardiac cell fate and cardiac disease. The specific aims of the proposal are: 1) To develop integration-free methods of human iPS cell generation for future cell-based therapies;2) To develop efficient directed differentiation of human iPS cells and methods of direct reprogramming into cell types relevant for future cell-based therapies directed at cardiovascular disease;and 3) to use iPS technology for discovery of human cardiovascular disease mechanisms and for drug discovery approaches. The integrated team assembled in this proposal will bring broad and critical expertise to the NHLBI Progenitor Cell Consortium in an effort to aggressively capitalize on the promise and potential of iPS cells for heart disease.